Genetic Variant LMX1B:p.Arg246Gln (chr9-126693319-G-A) – ACMG Classification: Pathogenic (19 pts)

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001174147.2(LMX1B):c.737G>A(p.Arg246Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R246P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LMX1B
NM_001174147.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 9.51

Publications

19 publications found

Variant links:

Genes affected

LMX1B (HGNC:6654): (LIM homeobox transcription factor 1 beta) This gene encodes a member of LIM-homeodomain family of proteins containing two N-terminal zinc-binding LIM domains, 1 homeodomain, and a C-terminal glutamine-rich domain. It functions as a transcription factor, and is essential for the normal development of dorsal limb structures, the glomerular basement membrane, the anterior segment of the eye, and dopaminergic and serotonergic neurons. Mutations in this gene are associated with nail-patella syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

LMX1B Gene-Disease associations (from GenCC):

nail-patella syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
nail-patella-like renal disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LMX1B links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001174147.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-126693319-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 812901.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 33 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 2.0208 (below the threshold of 3.09). Trascript score misZ: 1.8847 (below the threshold of 3.09). GenCC associations: The gene is linked to nail-patella-like renal disease, nail-patella syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

PP5

Variant 9-126693319-G-A is Pathogenic according to our data. Variant chr9-126693319-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 498798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001174147.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LMX1B	NM_001174147.2	MANE Select	c.737G>A	p.Arg246Gln	missense	Exon 4 of 8	NP_001167618.1	O60663-1
LMX1B	NM_001174146.2		c.737G>A	p.Arg246Gln	missense	Exon 4 of 8	NP_001167617.1	O60663-3
LMX1B	NM_002316.4		c.737G>A	p.Arg246Gln	missense	Exon 4 of 8	NP_002307.2	O60663-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LMX1B	ENST00000373474.9	TSL:1 MANE Select	c.737G>A	p.Arg246Gln	missense	Exon 4 of 8	ENSP00000362573.3	O60663-1
LMX1B	ENST00000355497.10	TSL:1	c.737G>A	p.Arg246Gln	missense	Exon 4 of 8	ENSP00000347684.5	O60663-3
LMX1B	ENST00000526117.6	TSL:1	c.737G>A	p.Arg246Gln	missense	Exon 4 of 8	ENSP00000436930.1	O60663-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

217784

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1444634

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717430

African (AFR)

AF:

0.00

AC:

AN:

32922

American (AMR)

AF:

0.00

AC:

AN:

42398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25792

East Asian (EAS)

AF:

0.00

AC:

AN:

38580

South Asian (SAS)

AF:

0.00

AC:

AN:

83962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52198

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4536

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104650

Other (OTH)

AF:

0.00

AC:

AN:

59596

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Nail-patella syndrome (3)

Nail-patella-like renal disease (2)

Nephrotic syndrome (2)

Inherited focal segmental glomerulosclerosis (1)

LMX1B-related disorder (1)

Nail-patella syndrome;C0403548:Nail-patella-like renal disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.9

PhyloP100

9.5

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MutPred

0.77

Gain of ubiquitination at K220 (P = 0.028)

MVP

0.95

MPC

1.8

ClinPred

1.0

GERP RS

5.0

Varity_R

0.84

gMVP

0.90

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over